INTRANASAL DELIVERY OF PEPTIDE DRUGS TO THE BRAIN Alzheimer's disease (AD) is a progressive and fatal neurological disorder that affects approximately one-tenth of the population over the age of 65. There is currently no cure for the disease. The pathological hallmarks of the disease include the formation and accumulation in the brain of ss-amyloid (Ass), widely recognized to be the major neurotoxic agent in AD. Earlier therapeutic attempts at lowering total Ass production were unsatisfactory as they directly targeted the catalytic activities of ss- or -secretase, enzymes known to hydrolyze other substrates as well as APP, many with critical cellular functions. New therapeutic approaches that can inhibit total Ass production without targeting the activities of the ss- or the -secretase are therefore of great interest. Cenna has a novel technology that does not target the secretases, which has yielded a potential peptide drug candidate, P8, with the ability to inhibit the production of Ass in vitro and in a Tg mouse model of AD, which could be developed as a new peptide drug for the treatment of AD. A significant challenge to the development of peptide drug candidates to treat disorders of the CNS, and critical to the development of P8, is that the systemic delivery of peptides to the CNS is not effective due to the presence of the blood brain barrier (BBB). There is evidence that intranasal delivery of peptides is a way to circumvent the BBB. Direct intranasal delivery of therapeutics to the brain is a non-invasive alternative to invasive delivery methods to by-pass the BBB, utilizing pathways along olfactory and trigeminal nerves innervating the nasal passages. In this application we propose to explore the delivery of P8 to the mouse brain by intranasal administration. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is a devastating degenerative neurological disorder that affects one-tenth of the population over the age of 65. There is no cure for the disease. Our overall goal is to further develop an 8-amino acid peptide, P8, that is active in vitro and in vivo in reducing the toxic species, Ass, into a new disease-modifying drug for the treatment of Alzheimer's Disease. In this application we will explore the delivery of P8 to the brains of mice by intranasal administration.